Magnetic resonance imaging enables noninvasive visualization of tissues and organs of the human body. Contrast in the images generated may be enhanced through the use of an agent that alters the relaxation of water in the tissues of interest relative to bulk water. Species with unpaired electrons, such as the paramagnetic transition and lanthanide metal ions, may be used for this purpose. Manganese chloride was investigated as a contrast agent by Lauterbur and by Wolf in animal models. Both investigators demonstrated significant image enhancement of the liver and other organs (but not blood) through the use of manganese chloride, but determined that the potential clinical utility of the agent was limited by acute cardiac toxicity. Development of contrast agents based on other paramagnetic metal ions is similarly constrained by toxicity and solubility. For instance, gadolinium chloride, acetate and sulfate demonstrate poor tolerability, including symptoms of heavy metal poisoning and accumulation of gadolinium in the liver, spleen and bone.
Chelates of paramagnetic transition and lanthanide metals have been used with some success in diagnostic imaging to overcome both the toxicity and solubility problems. (See U.S. Pat. No. 4,647,447.) Application of this technology has enabled the development of several gadolinium based MR contrast agents including Gd-DTPA (Magnevist.TM., Schering), Gd-DTPA-BMA (Omniscan.TM., Nycomed Amersham PL), Gd-HP-DO3A (Prohance.TM., Bracco Diagnostics) and Gd-DOTA (Dotarem.TM., Guerbet), as well as the manganese-based contrast agent MnDPDP (Teslascan.TM., Nycomed Amersham PL). There are, however, drawbacks associated with the use of chelation to solve problems of toxicity. Metals ions are not irreversibly held in chelate complexes, but are subject to equilibrium between bound and free states. In vivo, this equilibrium is further complicated by equilibria between the chelator and endogenous metal ions as well as between the paramagnetic metal ion and endogenous ligands. Greis, in U.S. Pat. No. 5,098,692 and Bosworth, in U.S. Pat. No. 5,078,986 disclose the use of excess chelator to minimize the amount of free metal ion in chelate-based diagnostic compositions. Nonetheless, the potential for the dissociation of metal ion from the complex remains. The free chelator, either excess or released, may introduce additional toxicity on its own or through chelation of those endogenous metal ions that are required as cofactors for essential enzymes or for other biological functions. Unfortunately, chelates also demonstrate reduced solution relaxivity relative to the free metal ions. The interaction of paramagnetic metal ions with water molecules, which shortens proton relaxation time relative to bulk water and gives rise to signal enhancement, is obtunded by chelation, since the same sites of metal-water interaction are used to form the non-covalent associations between metal and chelate. Thus chelation provides safety at the price of reduced imaging efficacy (compared to the free metal ion). In practice this loss of efficacy may be as high as 60-80%.
Manganese chelate image enhancement agents are known: e.g MnDPDP, MnDTPA, MnEDTA and derivatives, Mn porphyrins such as MnTPPS.sub.4, and fatty acyl DTPA derivatives. These manganese chelates are not known to bind to endogenous macromolecules, as is the case for manganese ion. As a consequence, the enhanced efficacy seen for Mn ion following macromolecular association is seen for Mn chelates only as a function of the rate at which and the extent to which the manganese ion dissociates from the complex. This results in the need for increased dosing of Mn chelates relative to free Mn ion. The dose must be additionally increased to make up for losses due to renal excretion of the chelate during the time course of the diagnostic examination. In a variation on chelation, Quay (European patent application 308983) has described the use of manganese amino acid coordination complex solutions. This application also discusses the addition of calcium ions to the manganese amino acid solutions at levels up to 0.75 mole equivalents relative to manganese.
About ten years ago, Schaefer et al investigated a mixture of Mn++ and Ca++ salts in the form of manganese gluconate and calcium gluconate in a one to one mole ratio, administered intravenously to dogs, for cardiac perfusion imaging. Although the agent discriminated normally perfused from ischemic tissue, Schaefer et al also noted acute cardiotoxicity similar to that seen with manganese chloride alone. The authors suggested that a possible way around the observed adverse cardiac effects might be to employ a chelate rather than a salt of manganese. No further studies employing manganese gluconate and calcium gluconate or other salts or complexes providing Mn++ and Ca++ in a higher ratio than one- to-one have subsequently appeared.
U.S. Pat. Nos. 5,525,326 and 5,716,598 describe oral manganese formulations for imaging of the gastrointestinal tract and for liver imaging; the latter takes advantage of the fact that the blood supply from the GI tract passes through the liver, which removes the manganese from the blood stream prior to return of the blood to the heart. Additional oral agents have been investigated, including manganese polymers, manganese impregnated molecular sieves, manganese clays and foodstuffs with high manganese content, such as blueberry juice. In general, cardiovascular safety is achieved for these agents at the expense of limiting the diagnostic utility of the agents to MR examination of the GI tract and in some cases, the liver. The administration of manganese in nanoparticulate form has been described in U.S. Pat. No. 5,401,492. Other particulate approaches include sequestration of Mn compounds in liposomes and metal clusters, such as manganese oxalate and manganese hydroxyapatite. Particulate agents are useful for a limited number of diagnostic applications, namely, the gastrointestinal tract and organs, such as the liver and the spleen, that are involved in the uptake and sequestration of blood borne particles.
Thus it would be useful to have an agent for diagnostic imaging of tissues, systems and organs, particularly in humans, that would increase the contrast in an MR image without giving rise to problems of toxicity. It would also be useful to have an agent that could be employed for a wide variety of tissues, systems and organs that are physiologically remote from the gastrointestinal tract.